The overall aim of this project is to develop therapeutics that will halt or slow the progression of Alzheimer's disease. The proposed project is based on the discovery of a novel neuroprotective mechanism that protects against the toxicity of AB, the agent implicated in the pathogenesis of Alzheimer's disease. We have demonstrated that cleavage products of sAPPa, derived from amyloid precursor protein (APP), are activators of this pathway. This data, combined with knowledge of the natural cleavage products of sAPPa, suggest that such peptide products are the natural mediators of this neuroprotective mechanism in the brain. In Phase I, we will demonstrate the feasibility of developing drugs based on this hypothesis. We will demonstrate assays to test activation of this pathway in vitro and in vivo. The activation by neuroactive peptide fragments of APP will be demonstrated. This will generate the methods and preliminary data for the identification of peptide-based drug candidates that should have a disease-modifying effect on Alzheimer's disease. The effectors of the neuroprotective pathway are known and will be used as biomarkers for the activation of this pathway. A quantitative and higher throughput enzyme-linked immunosorbent assay will be developed using a model neural culture system. In addition, the intraparenchymal injection of compounds will be performed to demonstrate the feasibility of testing compounds in vivo. Potential technological innovation: This project will generate novel methods for testing compounds for activation of a neuroprotective pathway. Moreover, candidate protective peptides will be identified based upon a tetrapeptide already shown to have activity. Anticipated results/outcomes: This project will demonstrate the feasibility of identifying neuroactive peptides based on the proteolytic products of the amyloid precursor protein and with potential efficacy against Alzheimer's disease. Potential commercial applications: Development of these peptides for intravascular injection and intracerebroventricular infusion would be the shortest route to the clinic and an important proof-of-principle. Based upon the mechanism of neuroprotection, patients with early onset Alzheimer's disease would particularly benefit from the developed therapeutics. Relevance to public health: Success in this project would provide enormous clinical and economic benefits. Alzheimer's disease is the most common cause of dementia, affecting an estimated 4.5 million Americans at national burden estimated to be $100 billion. Therapies developed from this project would bring enormous benefits to individuals, families, and society as a whole. [unreadable] [unreadable] [unreadable]